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OHSU Discovery Helps Solve Weight Loss Drug Mystery

07/20/06 Portland, Ore.

Research helps explain how many weight loss drugs work.

Researchers at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University have discovered the specific mechanisms in the body that allow certain weight loss drugs to work. Until now, the exact methods in which these drugs affect weight have been unknown. The research is printed in the July 20 edition of the scientific journal Neuron.

"Researchers have long known that drugs which increase the levels of the body chemical serotonin, such as the now recalled drug fenfluramine and the drug sibutramine, also have an effect on body weight," explained Michael Cowley, Ph.D., an assistant scientist in the Division of Neuroscience at ONPRC. "However, we lacked specific knowledge as to how this exactly occurs. Now we have an answer.

" By studying mice, which have been shown to be excellent models for human obesity studies, the scientists traced the pathway that these drugs take in the body. In doing this, the scientists learned that these "serotonin stimulators" affected two types of neurons in the brain: those that are involved in appetite stimulation called AgRP, and those that curb appetite called MSH. Specifically, the drugs reduced the stimulation of AgRP while increasing stimulation of MSH. The impacts on AgRP and MSH production then impacted the receptors for a body chemical called melanocortin that is involved in the control of appetite. By interrupting the natural impacts of melanocortin on the body, this chain of events allows these drugs to work and for weight loss to occur.

A secondary discovery for the researchers was that the serotonin pathway impacts the melanocortin-4 receptor but not the melanocortin-3 receptor. This finding gives researchers a much clearer view of how appetite stimulation and interruption occurs.

"In the case of fenfluramine, the drug caused strong weight loss but also caused heart valve problems leading to its recall," explained Cowley. "We hope that a better understanding of this system will allow for the development of better and safer weight loss drugs in the future."

The ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International.